Virus World

June 7, 2024—CDC has completed its initial study of the effects of the A(H5N1) bird flu virus from the human case in Texas on ferrets, a model used to assess potential impact on people.

What you need to know

• The A(H5N1) virus from the human case in Texas caused severe illness and death in ferrets. A(H5N1) infection in ferrets has been fatal in the past. This is different from what is seen with seasonal flu, which makes ferrets sick, but is not lethal.
• The A(H5N1) virus from the human case in Texas spread efficiently between ferrets in direct contact but did not spread efficiently between ferrets via respiratory droplets. This is different from what is seen with seasonal flu, which infects 100% of ferrets via respiratory droplets.
• These findings are not surprising and do not change CDC’s risk assessment for most people, which is low. The results do reinforce the need for people who have exposure to infected animals to take precautions and for public health and agriculture communities to continue to work together to prevent the spread of the virus to additional dairy herds and people.

CDC researchers used a ferret model[1] to better understand the severity of illness and efficiency of transmission of A/Texas/37/2024. For decades, CDC has conducted these types of studies to inform risk assessments of influenza viruses with pandemic potential. CDC used the virus from the human case in Texas which was reported on April 1, 2024, and was associated with sick dairy cow exposure. These are the first publicly reported animal model findings from a virus that infected a human as part of the current multistate outbreak of A(H5N1).

Summary of study findings

The study, completed on Friday, May 31, found that A/Texas/37/2024 virus caused severe disease (100% lethal) in all six ferrets that were infected. This is consistent with what has been found recently in ferret studies with A(H5N1) viruses, including two published studies conducted in the past year. Ferrets infected with A(H5N1) viruses from mink in Spain (A/mink/Spain/3691-8_22VIR10586-10/2022) and from a person in Chile (A/Chile/25945/2023) had severe illness that was either fatal or required euthanasia.

In terms of spread, the CDC ferret study found that the A/Texas/37/2024 virus spread easily among ferrets (3 of 3 ferrets, or 100%) in direct contact with infected ferrets (placed in the same enclosure). However, the virus was less capable of spreading by respiratory droplets, which was tested by placing infected ferrets in enclosures next to healthy ferrets (with shared air but without direct contact). In that situation, only 1 of 3 ferrets (33%) became infected, and there was a one- or two-day delay in transmission with the A/Texas/37/2024 virus compared to transmission with seasonal flu viruses. This suggests that A/Texas/37/2024-like viruses would need to undergo changes to spread efficiently by droplets through the air, such as from coughs and sneezes. CDC is repeating the experiment to confirm the findings and the results of these experiments will be used to inform an ongoing, broader CDC-led influenza risk assessment (IRAT) on A/Texas/37/2024.

In terms of direct contact spread, the mink virus from Spain caused efficient spread (100%) among ferrets. The study using the Chile virus found 75% spread by direct contact among ferrets. While the findings related to respiratory transmission were similar in that there was no efficient respiratory spread, there were differences in terms of whether any respiratory spread was observed or not. The study cited previously using A/mink/Spain/3691-8_22VIR10586-10/2022 found 37.5% transmission by respiratory droplets. The study using A/Chile/25945/2023 found no transmission by respiratory droplets. The most recent CDC findings are more consistent with the findings with the mink virus from Spain than the virus from Chile. (Additional information about ferret transmission findings with avian influenza is available below.)

Conclusion and risk assessment

Taken together, these findings underscore that the A(H5N1) viruses spreading in poultry, dairy cows, and other animals with sporadic human infections pose a serious potential public health risk and could cause serious illness in people. While the three cases of A(H5N1) in the United States have been mild, it is possible that there will be serious illnesses among people. Findings from this study are largely consistent with recent A(H5N1) studies in ferrets, as well as past reports of serious human illness resulting from this virus. These findings also suggest; however, that current A(H5N1) viruses would need to undergo genetic changes to spread more easily via respiratory droplets, which is reassuring. Efficient respiratory droplet spread, like what is seen with seasonal influenza viruses, is needed for sustained person-to-person spread to happen. These findings do not change CDC’s immediate risk assessment for the general public who do not have animal exposures, which is low.

Respiratory droplet spread compared

There have been several prior respiratory droplet spread in ferrets with avian influenza viruses. Selected studies:

• A study done using the avian influenza A(H7N9) virus (which has the highest pandemic risk assessment score on CDC’s Influenza Risk Assessment Tool (IRAT)) found that “A/Hong Kong/125/2017” spread easily among ferrets in the same enclosure but only 1 of 3 ferrets in the adjacent enclosure became via respiratory droplets in that study.
• A 2006 CDC study summarized results of a ferret study on A/Hong Kong/486/97, an A(H5N1) virus isolated from a human case in 1997. That study found respiratory droplet spread occurred in 2 of the 3 ferrets (66%). At that time, A(H5N1) viruses had caused probable person-to-person spread. That older 1997 A(H5N1) virus did not emerge to spread efficiently among people. Person-to-person spread has not been observed with A(H5N1) viruses since 2007.
• The previously mentioned 2024 study evaluated an A(H5N1) virus that caused an outbreak among mink at a mink farm in Spain (“A/mink/Spain/3691-8_22VIR10586-10/2022”) and found that respiratory droplet spread occurred in 3 out of 8 ferrets (37.5%). Of note, this study used a side-to-side airflow methodology; by contrast, CDC uses a top-to-bottom airflow approach. Despite the differences in methods, the results from this study were similar to those found in the CDC study.
• The most recently published CDC A(H5N1) ferret study was conducted on a virus from a human A(H5N1) case in Chile. Investigators found efficient direct contact spread, but no respiratory droplet spread.
• On the lowest end of the pandemic risk assessment scale, another ferret study looked at the effects of a low pathogenic avian influenza A(H7N9) virus (A/chicken/Tennessee/17-007431-3/2017) isolated from a multistate poultry outbreak in the United States with no human infections. There was inefficient spread in the direct contact model, with only 1 of 3 co-housed ferrets becoming infected. Because spread in the direct contact model was inefficient, spread by respiratory droplets was not studied.

Background on Ferret Studies

Ferrets are considered the best small mammal for studying influenza virus infection and transmission and are commonly used as a tool to inform public health risk assessments of emerging influenza viruses. In these studies, ferrets are experimentally infected and followed to assess severity of illness. To test the ability of the virus to spread, infected ferrets are exposed to healthy ferrets in different settings. Understanding the disease characteristics of novel influenza viruses and their capacity to spread is a critical component of any public health response.

Agriculture minister says origins of outbreak unclear after seven farm workers – and 87% of the mink – test positive. Spain has ordered the culling of nearly 100,000 mink on a farm after confirming many were carrying coronavirus, a regional minister said on Thursday. Joaquin Olona, agriculture minister for the north-eastern Aragon region, said the cull would involve the slaughter of 92,700 mink which are prized for their pelt.

Officials suspect the virus first reached the farm through a worker who passed it on to the animals. But Olona said it was not completely clear if “transmission was possible from animals to humans and vice versa”. In the Netherlands tens of thousands of mink have been slaughtered since the start of the pandemic after 20 farms were found to be infected, the Dutch authorities said earlier this month. The move came after at least two farm workers were found to be infected in May, most likely by the mink, with the World Health Organization saying it could be the first known cases of animal-to-human transmission.

In Spain the mink farm – in Puebla de Valverde, about 100km (60 miles) north-west of the coastal resort of Valencia – has been carefully monitored since 22 May after seven workers tested positive for Covid-19, Olona said. Since then no animals have left the property, which is the only mink farm in Aragon. Officials have since carried out a string of PCR tests which on 13 July showed that 87% of the mink were infected, prompting the decision to carry out a cull “to avoid the risk of human transmission”, Olona said....

Ferrets got two doses of a solution - which contains an artificial molecule designed to activate the immune system - during the trial. The spray is set to enter human trials in four months. Results reveal it slashed the virus' replication in their noses and throats by 96 per cent, reducing the risk of infection and cutting the odds of transmission.  The artificial compound — named INNA-051 — is set to enter human trials within the next four months. It was first developed to help protect against the common cold and flu, but is yet to be rubber-stamped because it has not been convincingly proven to work.  Previous research showed it 'accelerated' anti-viral responses in throat cells from healthy volunteers and those suffering from asthma, and provided 'prolonged protection' to mice from rhinoviruses, which cause runny noses in humans. If approved, the treatment could offer added defences to those at elevated risk from Covid-19 including the elderly and those with underlying health conditions.

A paper detailing the trial on INNA-051 has been published on the research website bioRxiv, although it is yet to be peer reviewed. The spray has been developed by Australian company Ena Respiratory, which first started work on the avant-garde treatment before the pandemic struck. It contains molecules designed to trigger TLR2 and TLR6 receptors on mucosal epithelial cells lining the throat and nose, attracting hordes of white blood cells to the area and boosting immunity.  The trial of the spray on the ferrets was led by Professor Miles Carroll, deputy director and head of research at Porton Down of Public Health England. Dr Christophe Demaison, managing director of Melbourne-based Ena Respiratory said: 'We've been amazed with just how effective our treatment has been. 'By boosting the natural immune response of the ferrets with our treatment, we've seen a rapid eradication of the virus.' He added: 'If humans respond in a similar way, the benefits of treatment are two-fold. 'Individuals exposed to the virus would most likely rapidly eliminate it, with the treatment ensuring that the disease does not progress beyond mild symptoms.

This is particularly relevant to vulnerable members of the community. 'In addition, the rapidity of this response means that the infected individuals are unlikely to pass it on, meaning a swift halt to community transmission.' The firm said if human trials prove successful and funding is secured, the therapy could be rapidly manufactured at scale. Professor Roberto Solari a respiratory specialist adviser to Ena Respiratory and visiting professor at Imperial College London, said: 'This is a significant development as the world races to find a solution to halt Covid-19 transmission and infection of at-risk populations. 'Most exciting is the ability of INNA-051 to significantly reduce virus levels in the nose and throat, giving hope that this therapy could reduce Covid-19 transmission by infected people, especially those who may be pre-symptomatic or asymptomatic and thus unaware they are infectious.'....

Preprint available in bioRxiv (Sept. 25, 2020):

https://doi.org/10.1101/2020.09.25.309914